This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jones, M. B. Articles by Kohn, E. C. Search for Related Content PubMed PubMed Citation Articles by Jones, M. B. Articles by Kohn, E. C.

The Granulin-Epithelin Precursor/PC-Cell-derived Growth Factor Is a Growth Factor for Epithelial Ovarian Cancer

Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892-1500 [M. B. J., C. M. M., J. O. B., M. R., M. R. E-B., D. B. K., L. A. L., E. C. K.]; Laboratory of Integrative and Medical Biophysics, National Institute of Child Health and Human Development, Bethesda, Maryland [V. A. K.,]; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland [G. S.]; Marlene and Stewart Greenebaum Cancer Center of the University of Maryland, Baltimore, Maryland [G. S.]; and Center for Biological Evaluation and Research, Food and Drug Administration, Bethesda, Maryland [E. F. P.]

Purpose: The role of growth factors in ovarian cancer development and progression is complex and multifactorial. We hypothesized that new growth factors may be identified through the molecular analysis of ovarian tumors as they exist in their native environment.

Experimental Design: RNA extracted from microdissected serous low malignant potential (LMP) and invasive ovarian tumors was used to construct cDNA libraries. A total of 7300 transcripts were randomly chosen for sequencing, and those transcripts were statistically evaluated. Reverse transcription-PCR and immunohistochemistry were used to validate the findings in tumor tissue samples. Ovarian cancer cell lines were used to test gene effects on monolayer growth, proliferative capacity, and density-independent growth.

Results: Analysis of the pooled library transcripts revealed 26 genes differentially expressed between LMP and invasive ovarian cancers. The granulin-epithelin precursor [GEP/PC-cell derived growth factor (PCDGF)] was expressed only in the invasive ovarian cancer libraries (P < 0.028) and was absent in the LMP libraries (0 of 2872 clones). All of the invasive tumor epithelia, 20% of the LMP tumor epithelia, and all of the stroma from both subsets expressed GEP by reverse transcription-PCR. Immunohistochemical staining for GEP was diffuse and cytosolic in invasive ovarian cancer tumor cells compared with occasional, punctate, and apical staining in LMP tumor epithelia. Antisense transfection of GEP into ovarian cancer cell lines resulted in down-regulation of GEP production, reduction in cell growth (P < 0.002), decrease in the S-phase fraction (P < 0.04), and loss of density-independent growth potential (P < 0.01).

Conclusion: cDNA library preparation from microdissected tumor epithelium provided a selective advantage for the identification of growth factors for epithelial ovarian cancer. Differential granulin expression in tumor samples and the antiproliferative effects of its antisense down-regulation suggest that GEP may be a new autocrine growth factor and molecular target for epithelial ovarian cancer.

This article has been cited by other articles:

				D. Tolkatchev, S. Malik, A. Vinogradova, P. Wang, Z. Chen, P. Xu, H. P.J. Bennett, A. Bateman, and F. Ni Structure dissection of human progranulin identifies well-folded granulin/epithelin modules with unique functional activities Protein Sci., April 1, 2008; 17(4): 711 - 724. [Abstract] [Full Text] [PDF]

				F. A. Simpkins, N. M. Devoogdt, N. Rasool, N. E. Tchabo, E. U. Alejandro, M. M.R.N. Kamrava, and E. C. Kohn The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells Carcinogenesis, March 1, 2008; 29(3): 466 - 472. [Abstract] [Full Text] [PDF]

				C. H. P. Ong, Z. He, L. Kriazhev, X. Shan, R. G. E. Palfree, and A. Bateman Regulation of progranulin expression in myeloid cells Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1602 - R1612. [Abstract] [Full Text] [PDF]

				M. B. Jones, A. P. Houwink, B. K. Freeman, T. M. Greenwood, J. M. Lafky, W. L. Lingle, A. Berchuck, G. L. Maxwell, K. C. Podratz, and N. J. Maihle The Granulin-Epithelin Precursor Is a Steroid-Regulated Growth Factor in Endometrical Cancer Reproductive Sciences, May 1, 2006; 13(4): 304 - 311. [Abstract] [PDF]

				P. C. Hanington, D. R. Barreda, and M. Belosevic A Novel Hematopoietic Granulin Induces Proliferation of Goldfish (Carassius auratus L.) Macrophages J. Biol. Chem., April 14, 2006; 281(15): 9963 - 9970. [Abstract] [Full Text] [PDF]

				N. Matsumura, M. Mandai, M. Miyanishi, K. Fukuhara, T. Baba, T. Higuchi, M. Kariya, K. Takakura, and S. Fujii Oncogenic Property of Acrogranin in Human Uterine Leiomyosarcoma: Direct Evidence of Genetic Contribution in In vivo Tumorigenesis Clin. Cancer Res., March 1, 2006; 12(5): 1402 - 1411. [Abstract] [Full Text] [PDF]

				E. M. Posadas, F. Simpkins, L. A. Liotta, C. MacDonald, and E. C. Kohn Proteomic analysis for the early detection and rational treatment of cancer--realistic hope? Ann. Onc., January 1, 2005; 16(1): 16 - 22. [Abstract] [Full Text] [PDF]

				S. T. Cheung, S. Y. Wong, K. L. Leung, X. Chen, S. So, I. O. Ng, and S. T. Fan Granulin-Epithelin Precursor Overexpression Promotes Growth and Invasion of Hepatocellular Carcinoma Clin. Cancer Res., November 15, 2004; 10(22): 7629 - 7636. [Abstract] [Full Text] [PDF]

				S. Chevillard, N. Ugolin, P. Vielh, K. Ory, C. Levalois, D. Elliott, G. L. Clayman, and A. K. El-Naggar Gene Expression Profiling of Differentiated Thyroid Neoplasms: Diagnostic and Clinical Implications Clin. Cancer Res., October 1, 2004; 10(19): 6586 - 6597. [Abstract] [Full Text] [PDF]

				W. Tangkeangsirisin and G. Serrero PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells Carcinogenesis, September 1, 2004; 25(9): 1587 - 1592. [Abstract] [Full Text] [PDF]

				W. Tangkeangsirisin, J. Hayashi, and G. Serrero PC Cell-Derived Growth Factor Mediates Tamoxifen Resistance and Promotes Tumor Growth of Human Breast Cancer Cells Cancer Res., March 1, 2004; 64(5): 1737 - 1743. [Abstract] [Full Text] [PDF]

				C.-X. Pan, M. S. Kinch, P. A. Kiener, S. Langermann, G. Serrero, L. Sun, J. Corvera, C. J. Sweeney, L. Li, S. Zhang, et al. PC Cell-Derived Growth Factor Expression in Prostatic Intraepithelial Neoplasia and Prostatic Adenocarcinoma Clin. Cancer Res., February 15, 2004; 10(4): 1333 - 1337. [Abstract] [Full Text] [PDF]